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Journal of Immune Based Therapies
and Vaccines
Open Access
Review
Dendritic cells: In the forefront of immunopathogenesis and
vaccine development – A review
Mansour Mohamadzadeh*
1
and Ronald Luftig
2
Address:
1
Department of Medicine, Tulane University Health Science Center, New Orleans, USA and
2
Department of Microbiology, Immunology
and Parasitology, Louisiana State University, New Orleans, USA
Email: Mansour Mohamadzadeh* - ; Ronald Luftig -
* Corresponding author
dendritic cellsimmunopathogenesisvaccine developmentTh1/Th2 cellsCD4
+
/CD8
+
T cellsvaccines
Abstract
Dendritic cellls (DCs) comprise an essential component of the immune system. These cells, as
antigen presenting cells (APCs) to naïve T cells, are crucial in the initiation of antigen specific
immune responses. In the past years, several DC subsets have been identified in different organs
which exert different effects in order to elicit adaptive immune responses. Thus, identification of

such DC subsets has led to a better understanding of their distribution and function in the body.
In this review, several key properties of the immunobiology, immunopathogenesis and vaccine
strategies using DCs will be discussed.
Review
Dendritic cellls (DCs) are a complex, heterogeneous
group of multifunctional APCs. DCs are leukocytes, dis-
tributed throughout lymphoid and non-lymphoid tissues,
in peripheral blood and afferent lymph vessels [1]. It has
been shown that DCs after activation with different stim-
uli achieve maturation, where they express high levels of
several molecules on the cell surface such as MHC class I
and II, accessory molecules CD40, CD80, CD86 and early
activation markers such as CD83. These cells do not pro-
liferate and after a certain time course they undergo apop-
tosis and will be replaced by a new pool of cells [1].
Functionally, DCs exert various effects on other immune
cells, particularly in secondary lymphoid organs; DCs
present non-self peptide-MHC complexes to naïve and
memory T lymphocytes to mobilize specific immunity [1-
4]. By contrast, in order to induce T cell-tolerance in the
thymus, DCs present self peptide-MHC complexes to thy-
mocytes [5]. The capacity of DCs to initiate primary
immune responses is due to their ability to deliver specific
costimulatory signals which are essential for T cell activa-
tion from the resting or naive state into distinct classes of
effector cells. These immunogen-specific immune
responses are critical for example, to tumor resistance,
prevention of metastasis, and blocking infections. DCs
also can alter the function of regulatory T cells that control
activated T cells through their suppressive signals. In addi-

tion, DCs play an important role in innate immunity by
secreting cytokines, e.g. IL-12 and Interferon classes I and
II, involved in host defense. Moreover, DCs activate Natu-
ral killer cells (NK) and NKT cells that rapidly eradicate
select targets [1]. Such diverse functions of DCs has begun
to shed light on their pre-eminent role in immunological
events. In this review we highlight several critical aspects
of DCs in order to better understand host-pathogen
interactions.
Published: 13 January 2004
Journal of Immune Based Therapies and Vaccines 2004, 2:1
Received: 03 December 2003
Accepted: 13 January 2004
This article is available from: />© 2004 Mohamadzadeh and Luftig; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are per-
mitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 2 of 11
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Origin and developmental processes of dendritic
cells
DCs originate from hematopoietic stem cells in the bone
marrow. Recently, there have been great insights into the
origins of DC subsets [6,7] and their modulation by dis-
tinct cytokines of neighboring cells [8,9]. Progenitors of
DCs in bone marrow migrate via the blood stream and
home to peripheral tissues where they encounter several
essential growth factors such as GM-CSF, IL-4, IL-15, TNF-
α, TGF-β, and IL-3 secreted by various cell types including
endothelial cells, Mast cells, keratinocytes and fibroblasts
in the microenvironment (Figure 1). Such growth factors
determine the fate of the progenitors to differentiate into

immature Langerhans DCs, interstitial DCs or plasmacy-
toid DCs (Figure 1).
One of the hallmarks of DC progenitors is their capacity
to migrate [10]. Cutaneous and nonlymphoid DC popu-
lations migrate to T-cell areas (Figure 2). For example,
cutaneous interstitial DCs enter mesenteric lymph nodes
[11]. Liver OX62
+
DCs, which reside in the portal triads
[12] and along the sinusoids [13], migrate into hepatic
lymph and subsequently to the celiac lymph nodes [14].
Experimentally it has been shown that isolated DCs from
several organs that were reinfused into animals, within 24
hrs, home to the T cell rich area of the draining lymph
nodes. Homed DCs sample and select very rare antigen
specific primary T cells from the recirculating stream [15].
In addition, DC subsets are ready to confront invading
pathogens [1]. In such environments DCs ingest antigens
via several mechanisms including phagocytosis [15] and
receptor-mediated endocytosis [16]. For example Langer-
hans DCs phagocytose, process, and present immuno-
genic peptides to T cells [1,16,17].
Antigenic infectious agents including vaccines induce pro-
inflammatory cytokines (e.g., TNF-α). These cytokines
promote Langerhans DC maturation in lymphoid organs
where they home to the T cell rich area [18]. Langerhans
DCs undergo phenotypic and functional changes during
their maturation and migration. These cells, which are
now loaded with antigenic peptides on MHC class II,
down-regulate CD1a, CCR6, and E-cadherin, and lose the

capacity to capture foreign antigens [9,18]. Mature DCs
are an end stage of differentiation, and they can not be
converted into either macrophages or lymphocytes.
DCs in general present marked heterogeneity in pheno-
type and function, which relate to their precise localiza-
tions within different tissues in the body. However, DCs
do not express phenotypic markers of T lymphocytes (e.g.
CD3, CD16, CD19, CD28), B cells (Ig and CD19, CD20),
or NK cells (CD 16, CD56, CD57). In some instances,
DCs express molecules that are also expressed on macro-
phages, and while the phenotypic distinction between
DCs and macrophages is not always clear; studies with
respect to their immunostimulatory functions (e.g., pri-
mary Mixed Lymphocyte Reaction) provide clear evidence
between these two types of antigen presenting cells. In
addition, DCs also express surface molecules which are
specifically expressed on T cell subsets (e.g., CD4), and a
DC subset residing in murine lymphoid organs express
CD8α marker [7].
Functions of dendritic cells
The role of DCs has been repeatedly highlighted in cancer
and infectious diseases [1]. Human CD14
+
progenitor
DCs cultured in GM-CSF+IL-4 are equivalent to interstitial
DCs (e.g., dermal DCs) and express CD1a, CD64 and Fac-
tor III a [16]. By contrast, monocytes cultured with M-CSF
convert to a monocyte/macrophage phenotype [18].
These myeloid DCs home within lymphoid follicles,
where they reside as germinal center DCs [19]. In this

area, germinal center DCs establish the contact between T-
and B-cells, which may lead to the stimulation of an active
immune response [20]. DCs present processed antigenic
peptides on MHC class II molecules to CD4
+
T cells [21],
which will be activated in conjunction with co-stimula-
tory signals (e.g., CD40, CD86) delivered from DCs in
lymphoid organs. Several receptors and their ligands are
involved in the T cell/DC dialogue, e.g., CD40/CD40L
[22]. For instance, up-regulation of CD40L on T cells facil-
itates DC maturation [23]. Activated DCs then release
cytokines such as IL-12, which modulate and stimulate
the production of IFN-γ from T cells [24]. Activated DCs
can either prime naive CD8
+
T cells, or they undergo apop-
tosis in situ [25]. Activated T cells migrate to the area of the
B-cell follicles via activated adhesion molecules [26-28].
There they interact with naïve antigen-specific B cells [29].
T- and B-cell interaction results in the clonal expansion of
B cells, which takes place in the plasma foci of the T cell
rich area [30] and in the germinal centers [31]. T- and B-
cell dialogue in the germinal center might be influenced
by germinal center DCs [20] and follicular DCs [30] (Fig-
ure 3).
Dendritic cells and T-cell tolerance
T cells before they encounter immunogenic antigens must
undergo a step where the T cell repertoire is tolerized to
self-antigen. This process when it occurs in the thymus is

called central tolerance. It occurs by deletion of develop-
ing T lymphocytes; in the lymphoid organs, it is called
peripheral tolerance by probably eliminating or anergiz-
ing committed mature T cells. In both situations, as dis-
cussed before, DCs not only induce primary antigen
specific T cell immune responses but these cells also
appear to induce tolerance of T cells to self-antigens. DCs
present self-antigen via MHC class molecules in the
thymic medulla. Experimentally it has been shown that if
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 3 of 11
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Human DC subsetsFigure 1
Human DC subsets. DC progenitors migrate from the bone marrow in the periphery and several different tissues. There
they encounter various growth factors which determine the fate of these cells to differentiate into immature DC subsets.
CD14
-
/CD11C
+
CD14
-
/CD11C
-
?
GM-CSF/
TNF/IL-4
TGF-
β
IL-3
Interstitial DC
Langerhans DC

Plasmacytoid DC
Subsets of Human Dendritic Cells
CD14
+
/CD11C
+
Monocytes
CD14
+
/CD11C
+
CD14
-
/CD11C
+
CD14
-
/CD11C
-
?
CD14
-
/CD11C
+
CD14
-
/CD11C
-
?
GM-CSF/

TNF/IL-4
TGF-
β
IL-3
Interstitial DC
Langerhans DC
Plasmacytoid DC
Subsets of Human Dendritic Cells
CD14
+
/CD11C
+
Monocytes
CD14
+
/CD11C
+
CD14
+
/CD11C
+
Monocytes
CD14
+
/CD11C
+
CD14
-
/CD11C
+

CD14
-
/CD11C
-
?
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antigen-loaded DCs are administrated to developing or
fetal thymus reactive T lymphocytes, they will be deleted
indicating that DCs play a critical role in this process.
Moreover, in the cortical area of the thymus, although
macrophages phagocytize dying T cells which did not
undergo positive selection these cells seem not to be
involved in deleting auto-reactive T cells. Studies show
that if MHC class II molecules are solely expressed by the
cortical epithelium and not by DCs residing in the
medulla, there is a higher probability towards an autoim-
mune disease. These results highlight the critical role of
DCs in educative processes of thymic T cells to self-anti-
gens. In addition, DCs play a critical role in peripheral tol-
erance by presenting self-antigen to T cells residing in
specialized tissues such as the pancreas [32,33]. Presenta-
tion of processed self-antigen as peptides by DCs ensures
T cell tolerance probably through T cell deletion or anergy
[32-34].
The role of dendritic cells in clinical diseases
Recent studies shed light on the role of DC involvement
in various diseases such as autoimmunity, allergy, trans-
plantation, infection and cancer. For example, studies
showed that DCs differentiated in vitro express very

important co-stimulatory molecules, e.g. CD40, which
allow these cells to approach T cells and deliver signals to
them [22,23]. With respect to that phenomenon,
Migration of immature DCs into lymphatic organsFigure 2
Migration of immature DCs into lymphatic organs. Skin surrounded by various immunogen antigens that can penetrate
the epidermis. These antigens can be captured by immature Langerhans DCs, and processed. Cutaneous DCs will then be acti-
vated, migrate, and home to the lymph nodes. Matured DCs present processed antigen to antigen specific T cells inducing spe-
cific immunity.
Antigen
Lymph node
Skin
Antigen
Lymph node
Skin
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cytokines (e.g., GM-CSF, TNF-α) produced by keratinoc-
ytes affect DC differentiation dramatically [35]. Moreover,
DCs alone produce essential cytokines (e.g. IL-1β, TNF-α,
IL-6), and chemokines MIP-1α, MIP-1γ, IL-15 and IL-8
[9,36-39]. Some of these cytokines contribute directly to
the DCs ability to attract and recruit T cells in sites of
inflammation. A number of autoimmune diseases (rheu-
matoid arthritis) or skin psoriasis demonstrates the accu-
mulation of DCs in diseased tissues [40]. This evidence
suggests that DC enrichment within the cytokine-rich syn-
osium or epidermis undergo phenotypic and functional
maturation in vivo. Furthermore, it seems that the ligation
of CD40 with DCs can enhance the antigen presenting
capacity of these cells [22]. It has recently been reported

that rheumatoid arthritis synovial T lymphocytes express
CD40L at a low level. These molecules can be dramatically
upregulated when T cells are activated. In this context,
stimulation of self-reactive T lymphocytes in the syno-
sium will be induced through GM-CSF and TNF-α along
with CD80
+
C086
+
DCs [41].
Induction of primary immune responses by DCsFigure 3
Induction of primary immune responses by DCs. The DC lineage comprises cells at different stages of differentiation
and development in different tissues. The currently accepted scheme suggests that DCs from bone marrow move via the blood
into non-lymphoid tissues. In these organs they undergo different changes with respect to shape, functions. In these organs
DCs induce primary T cell immune responses.
D
C
p
r
o
g
e
n
i
t
o
r
DC progenitor
NK
T

Macrophage
Ag-capture of Immature DC
T
Eosinophils
Mature DC Ag-presentation
T
B
B cell Follicle
T
T
T
B
T
Inflamed vessels
Ag
B
D
C
p
r
o
g
e
n
i
t
o
r
D
C

p
r
o
g
e
n
i
t
o
r
DC progenitorDC progenitor
NK
T
MacrophageMacrophageMacrophage
Ag-capture of Immature DC
T
Eosinophils
Mature DC Ag-presentation
T
B
T
B
B cell Follicle
T
T
T
T
T
B
T

Inflamed vessels
Ag
B
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 6 of 11
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As mentioned above, cytokines can control the develop-
ment and differentiation of DCs. For example, the
combination of GM-CSF and TNF-α can promote
differentiation of CD34
+
blood stem cells into DCs in
humans [6]. Phenotypically these cells are CD4
+
CD11C
+
since Langerhans DCs and other DC family numbers
express CD4 molecules that can bind to the HIV surface
envelope protein gp 120 [42]. This makes a possibility
stronger that DCs may contribute to HIV pathology. On
one hand, in vivo and in vitro experiments indicate that
the replication of HIV-1 virus occurs during cognate CD4
+
T cell activation through DCs. On the other hand, there is
evidence that the features of HIV pathology are an accu-
mulation of HIV virus in the germinal centers, which is T
cell rich and where a novel DC population has recently
been identified [20]. Both the APC function of DCs and
their close interaction with CD4
+
T cells suggests that ger-

minal centers of lymph nodes may provide an additional
site for HIV viral replication [42-44].
Moreover, DCs in transplanted organs are involved and
they represent potent "passenger leukocytes" that sensi-
tize host graft antigens and trigger rejection [45]. Studies
have shown that the depletion of DCs from mouse islets
or thyroid tissue prolonged survival in allogeneic recipi-
ents [45]. Other studies on the function of DCs after trans-
plantation of skin and heart tissues to allogeneic
recipients have shown that soon after grafting, DCs enter
the recipient's lymphoid tissues [46]. Thus, there appears
to be a sensitization of host T cells which occurs primarily
in these tissues when they encounter the graft-derived, all-
ogeneic DCs. Austyn et al. showed recently that host DCs
can also present graft antigens to host T cells [46]. In this
process it seems that host DCs bearing graft molecules
would migrate into the secondary lymphoid organs to
sensitize and activate T lymphocytes and induce graft
rejection.
It is clear now, that cancer cells can express tumor associ-
ated antigens, which are recognized by host T cells. These
T cells may not be able to reject tumor cells. These mole-
cules, then, are not immunogenic. In order to become
immunogenic they must be processed and presented by
professional antigen presenting cells (APC). Since DCs
possess relevant features, e.g. a) internalizing of immuno-
genic antigen through endocytosis, b) phagocytosis for
subsequent processing and presentation of several anti-
gens to T cells, and c) migration capability, they could
acquire tumor antigen.

In the past few years the role of DCs in cancer has been
suggested. There is evidence that DCs can induce immu-
nity to tumors if they are administrated to animals or
exposed to tumor associated antigen (TAA) before or
when the tumor is inoculated into animals [47-49]. For
example, Boczkowski et al. [50] conducted several elegant
experiments to demonstrate that DCs pulsed with synthe-
sized chicken ovalbumin (OVA) RNA were more effective
than OVA peptide-pulsed DCs in activating primary OVA
specific-CTL responses in vitro. This finding shows that the
amplification of antigens from a small number of tumor
cells is feasible, thus increasing the possibility of utilizing
RNA-pulsed DC based vaccines for patients bearing very
small tumors [50].
Studies demonstrate that when DCs are pulsed with
tumor antigens in ex vivo, and these cells subsequently
readministrated, specific immunity is established [51]. In
addition, several studies showed that tumor-specific CD8
+
cytotoxic T lymphocytes (CTL) constitute an important
effector arm of the anti-tumor immune response [52,53].
In this context to elicit specific immunity against tumor
cells, DCs were pulsed with protein or peptide in the pres-
ence of lipid [54] or transfected with DNA [55] were capa-
ble of eliciting primary CTL responses in vitro.
Although prior investigations have established that target-
ing immune cells to tumors may improve immunity [47-
55], in the case of DCs, however, it has been shown [56-
62] that the tumor microenvironment is detrimental to
DC function, and in fact may condition DCs to induce a T

cell response that anergizes or suppresses tumor-specific
immunity [56]. Thus, targeting DCs directly to tumors, as
demonstrated by several studies, may be inefficient.
Therefore, methods should be developed in order to target
DCs by immunogenic TAAs outside the tumor microenvi-
ronment to improve immunity.
Vaccine design by targeting dendritic cells
Given the central role of DCs in controlling immunity,
has brought a scientific focus to the critical role of DCs as
an efficient vector in vaccine technology. Several
approaches to target DCs efficiently have been designed.
There is a large body of literature involving experimental
animal models and for tumors and infection in which DC
subsets pulsed with TAAs or subunits of the pathogens
such as HCV or HIV are to induce protective immunity
against tumors. However, it is even more important to cre-
ate novel strategies by targeting immunogenic antigens or
immune regulatory agents specifically to DCs without
impairing the functional properties of DC subsets and in
this way modulate the immune responses in vivo.
These novel strategies must not be too costly, not immu-
nopathogenic, but specific in order to overcome anergy
established through negative signals which may be pro-
vided by immune component cells including DCs to the
microenvironment.
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 7 of 11
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One possible strategy is to target novel molecules
expressed on the cell surface of DCs. In this, we and others
utilized phage display peptide library to generate small

peptides which solely bind to DC subsets and not other
cells. DNA sequences encoding DC-peptides can then be
fused genetically with TAA coding regions or with the sub-
unit of the pathogen of interest. Immunogenic fusion pro-
teins can be then expressed by probiotic microorganisms
such as Lactobacilli or attenuated strains of Salmonella in
vivo (Figure 4). Such novel vaccine strategies should take
advantage of mucosal sites in the body, as well as the skin
in order to be delivered specifically to DC subsets in vivo
(Figure 5).
The Peyer's patch is the primary mucosal site for antigen
processing in the intestine. Recent in vivo studies provide
evidence that DC network in the subepithelial dome of
Peyer's patches is a critical component in the uptake and
processing of luminal antigens. Such uptake may occur by
endocytosis or by phagocytosis after passage of antigen
through M cells. The DCs then present the processed anti-
gen to CD4
+
or CD8
+
T cells in the subepithelial dome, or
after maturation and migration, to the interfollicular
regions where antigen is presented to CD4
+
/CD8
+
T cells
[63]. In this regard, immunohistologic analysis of DC
subsets including LCs in Peyer's patch has revealed that

the unique microanatomical localization of DC subsets
Delivery of immunogenic antigen to DCs by probiotic microorganismsFigure 4
Delivery of immunogenic antigen to DCs by probiotic microorganisms. DNA encoding sequences of DC-binding
peptides and immunogenic subunit of any pathogen will be expressed in Gram positive bacteria including Lactobacillus. Lactoba-
cillus will be orally administrated. These bacteria colonize the gut and express and release the immunogen in the intestine. DCs
in the mucosal site will then capture the immunogen via DC-binding peptide motifs. They internalize the immunogen, process
and present it to T cells inducing specific responses against released immunogen.
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 8 of 11
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enables them to regulate specific T- and B-cell responses in
vivo [63-65]. Other, studies also clearly demonstrated that
Gram-positive bacteria such as Lactobacilli can successfully
be used in order to deliver vaccine peptides to immune
component cells [66-68].
More specifically, in order to target any vaccine to DCs,
recently, a novel strategy was proposed. Mohamadzadeh
et al. fused a subunit of hepatitis C virus with a DC-bind-
ing peptide. Studies are ongoing to express such immuno-
genic fusion proteins by a strain of Lactobacilli [69]. Such
a Lactobacillus strain will express and secretes the immuno-
genic protein in the intestinal region. DCs will be able to
capture such immunogen via the motifs of DC-binding
peptides. Such binding of an immunogen to DCs will
facilitate rapid internalization of the immunogen into
DCs. DCs will then process and present it to T cells resid-
ing in the gut. These cells will be activated and will circu-
late through the body in order to elicit specific T cell
immune responses against the pathogen of interest.
A transdermal delivery system also offers an interesting
route to approach DC subsets in order to enhance immu-

nity against cancer or pathogens. Accordingly, the
immune system of the skin harbors two very potent anti-
gen-presenting DC subsets which induce primary antigen
specific T cell immune responses [70]. Furthermore, care-
ful experimentation of various vaccine delivery routes has
shed light on the skin and its immune mechanisms. It has
previously been shown that cutaneous DC subsets can be
Transdermal delivery of immunogenic fusion protein by cutaneous DCsFigure 5
Transdermal delivery of immunogenic fusion protein by cutaneous DCs. Genetically engineered immunogenic fusion
protein can be transdermaly administrated into the skin whereby cutaneous DC subsets can capture it via DC-peptide motifs
fused to immunogen subunits. Loaded cutaneous DC subsets can be activated, leave the skin and enter the lymph nodes where
they can present processed antigen as immunogenic peptides to T cells eliciting specific T cell immune responses.
Skin
Lymph Node
Antigen DC-pep
Skin
Lymph Node
Antigen DC-pepAntigen DC-pep
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 9 of 11
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targeted and activated in situ in order to achieve specific T
cell mediated immune responses [70-74]. Thus, the feasi-
bility of using immunogenic DC-peptide fusion proteins
should be tested to determine whether administration of
such immunogenic fusion proteins will induce the activa-
tion of cutaneous DC subsets that in turn prime antigen-
specific T cells in situ.
DCs play a crucial role in host-pathogen interactions. A
recent example [75] involves the report in human papil-
loma virus 16 which is strongly associated with the devel-

opment of cervical cancer, that in infected cells the E6
oncogenic protein limits the numbers of LC in infected
epidermis. This appears to decrease the host's ability to
mount an effective immunological response to HPV 16.
We anticipate that future studies will be focused on
enhancing functional aspects of DCs to prevent such
events and establish novel vaccine strategies to efficiently
target immunogenic antigens or inhibitory agents to DCs
in order to elicit or suppress specific immune responses in
vivo.
Conclusions
1. Dendritic cells play a significant role in
immunopathogenesis.
2. The functions of dendritic cells involve cancer, infec-
tious diseases and tolerance.
3. Novel approaches in vaccine design can occur by target-
ing dendritic cells.
Competing interests
None declared.
Author's contributions
Dr. M. Mohamadzadeh is the corresponding author and
designed the draft of the manuscript. Dr. R. Luftig contrib-
uted to the viral-related segments and overview of the
manuscript. Both authors read and approved the final
manuscript.
Abbreviations
TNF: Tumor Necrosis Factors
GM-CSF: Granulocyte macrophage colony stimulating
Factor
CD: Cluster Density

IL-1: Interleukin-1
TGF: Transforming growth factor
Acknowledgements
Dr. Mohamadzadeh acknowledges support from National Institute on Drug
Abuse (NIDA). Dr. Luftig acknowledges LSUHSC Institutional Funds.
References
1. Banchereau J, Steinman R: Dendritic cells and the control of
immunity. Nature 1998, 392:245-252.
2. Steinman RM: The dendritic cell system and its role in
immunogenicity. Annu Rev Immunol 1991, 9:271-296.
3. Austyn JM: Lymphoid dendritic cells. Immunol 1987, 62:161-170.
4. Metly JP, Pure E, Steinman RM: Control of the immune response
at the level of antigen-presenting cells: a comparison of the
function of dendritic cells and B lymphocytes. Adv Immunol
1989, 47:45-116.
5. Fairchild PJ, Austyn JM: Thymic dendritic cells: phenotype and
function. Intern Rev Immunol 1990, 6:187-196.
6. Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J: GM-CSF
and TNFα cooperate in the generation of dendritic Langer-
han cells. Nature 1992, 360:258-261.
7. Maraskovsky E, Brasel K, Teepe M, Roux ER, Lyman SD, Shortman
KD, McKenna HJ: Dramatic increase in the numbers of func-
tionally mature dendritic cells in Flt3-Ligand treated mice:
multiple dendritic cell sub-populations identified. J Exp Med
1996, 184:1953-1961.
8. Caux C, Banchereau J: In vitro regulation of dendritic cell devel-
opment and function. In Blood Cell Biochemistry, Hemopoietic growth
factors and their receptors Volume 7. Edited by: Whetton A, Gordon J. Ple-
num Press, London; 1996.
9. Mohmadzadeh M, Berard F, Essert G, Chaloini C, Pulendran B, Dav-

oust J, Palucka K, Banchereau J: IL-15 skews monocytes differen-
tiation into dendritic cells with features of Langerhans cells.
J Exp Med 2001, 194:1013-1019.
10. Larsen CP, Morris PJ, Austyn JM: Migration of dendritic leuko-
cytes from cardiac allografts into host spleen. A novel path-
way for initiation of rejection. I Exp Med 1990, 171:307-314.
11. Fossum S: Lymph-borne dendritic leukocytes do not recircu-
late, but enter the lymph node paracortex to become inter-
digitating cells. Scand J Immunol 1989, 27:97-105.
12. Matsuno K, Ezaki T, Kudo S, Uehara Y: A life stage of particle-
laden rat dendritic cells in vivo: their terminal division, active
phagocytosis and translocation from the liver to hepatic
lymph. J Exp Med 1996, 183:1865-1878.
13. Kudo S, Matsuno K, Ezaki T, Ogawa M: A novel migration path-
way for rat dendritic cells from the blood: Hepatic sinusoids-
lymph translocation. J Exp Med 1997, 185:777-784.
14. Brenan M, Puklavec M: The MRC OX-62 antigen: A useful
marker in the purification of rat veiled cells with the bio-
chemical properties of an integrin. J Exp Med 1992,
175:1457-1465.
15. Austyn JM: New insights into the mobilization and phagocytic
activity of dendritic cells. J Exp Med 1996, 183:1287.
16. Sallusto F, Cella M, Danielli C, Lanzavecchia A: Dendritic cells use
macropinocytosis and mannose receptor to concentrate
antigen in the MHC class II compartment. Downregulation
by cytokines and bacterial products. J Exp Med 1995,
182:389-400.
17. Mohamadzadeh M, Pavlidou A, Enk A, Knop J, Ruede E, Gradehandt
G: Freshly isolated mouse 4F7
+

splenic dendritic cells process
and present exogenous antigens to T cells. Eur J Immunol 1994,
24:3170.
18. Cella M, Sallusto F, Lanzavecchia A: Origin, maturation and anti-
gen presenting function of dendritic cells. Curr Opin Immunol
1997, 9:10-16.
19. Grouard G, Rissoan M, Filguera L, Durand I, Banchereau J, Liu YJ: The
enigmatic plasmacytoid cells develop into dendritic cells
with interleukin 3 and CD40-ligand. J Exp Med 1996,
185:1101-1111.
20. Grouard G, Durand I, Filgueira L, Banchereau J, Liu Y-J: Dendritic
cells capable of stimulating T cells in germinal centres. Nature
1996, 384:364-366.
21. Dubois B: Dendritic cells enhance growth and differentiation
of CD40-activated B Lymphocytes. J Exp Med 1997,
185:941-951.
22. Cella MD, Scheidegger D, Lehmann K, Lane P, Lanzavecchia A, Alber
G: Ligation of CD40 on dendritic cells triggers production of
Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 10 of 11
(page number not for citation purposes)
high levels of interleukin 12 and enhances T cell stimulatory
capacity: T-T help via APC activation. J Exp Med 1996,
184:741-747.
23. Grewal IS, Flavell RA: A central role for CD40 ligand in the reg-
ulation of CD4+ T cell responses. Immunol Today 1996,
17:410-414.
24. Mackey MF, Gunn JR, Maliszewski CR, Kikutani H, Noeller RJ, Barth
JR: DC require maturation via CD40 to generate protective
anti-tumor immunity. J Immunol 1998, 161:2094-2098.
25. Schoenberger SP, Toes REM: T-cell help for cytotoxic T lym-

phocytes is mediated by CD40-CD40L interaction. Nature
1998, 393:480-483.
26. Weiss JM, Sleeman J, Penkl H, Dittmar C, Termeer C, Taxis S, How-
ellset N, Simon JC: An essential role for CD44 variant isoforms
in epidermal Langerhans cell and blood dendritic cell
function. JC Bio 1997, 137:1137-1147.
27. Kelso A: Th1/Th2 cells: Paradigms lost. Immunol Today 1995,
16:374-379.
28. Kelsoe G, Zengh B: Sites of B-cell activation in vivo. Curr Opin
Immunol 1993, 5:418-422.
29. Pulendran B, Karvelas M, Nossal GJV: A form of immunologic tol-
erance through impairment of germinal centers. Proc Natl
Acad Sci USA 1994, 91:2639-2643.
30. Liu Y-J, Grouard G, de Bouteiller O, Banchereau J: Follicular den-
dritic cells and germinal centers. Int Rev Cytol 1996, 166:139-179.
31. Lombardi T: Langerhans cell: structure, function and role in
oral pathological conditions. J Oral Pathology Med 1993,
22:193-202.
32. Kurts C: Constitutive class I-restricted exogenous presenta-
tion of self antigen in vivo. J Exp Med 1996, 184:923-930.
33. Kurts C, Kosaka H, Carbone ER, Miller JE, Heath WR: Class-I
restricted cross-presentation of exogenous self antigens
leads to deletion of autoreactive CD8+ T cells. J Exp Med 1997,
186:239-245.
34. Forster I, Lieberam I: Peripheral tolerance of CD4 T cells fol-
lowing local activation in adolescent mice. Eur J Immunol 1996,
26:3194-3202.
35. Caux C, Vanbervliet B, Massacrier C, Dezutter-Dambuyant C, de
Saint-Vis B, Jacquet C, Yoneda K, Imamura S, Schmitt D, Banchereau
J: CD34+ hematopoietic progenitors from human cord blood

differentiate along two independent dendritic cell pathways
in response to GM-CSF + TNFα. J Exp Med 1996, 184:695.
36. Sallusto F, Lanzavecchia A: Efficient presentation of soluble anti-
gen by cultured human dendritic cells is maintained by gran-
ulocyte/macrophage colony-stimulating factor and
downregulated by tumour necrosis factor a. J Exp Med 1994,
179:1109-1117.
37. Caux G, Vanbervliet B: Regulation of dendritic cell recruitment
by chemokines. 1994, 73:S7-11.
38. Mohamadzadeh M, Takashima A, Dougherty I, Knop J, Bergstresser
PR, Crus PD Jr: Ultraviolet B radiation up-regulates the
expression of IL-15 in human skin. J Immunol 1995,
155:4492-4496.
39. Mohamadzadeh M, Poltak AN, Bergstresser PR, Beutler Takashima
BA: Dendritic cells produce macrophage inflammatory pro-
tei 1 g, a new member of the CC chemokine family. J Immunol
1996, 156:3102-3106.
40. Mitra RS, Judge TA, Nestle FO, Turka LA, Nikoloff BJ: J Immunol 1995,
154:2669-2677.
41. Lipsky PE, Davis LS, Cuah JJ, Oppenheimer-Marks: Springer Semin.
Immunopathol 1989, 11:123-162.
42. Dalgleish AG, Beverley PCL, Clapham PR, Crawford DH, Greaves
MF, Weis RA: The CD4 (T4) antigen is an essential component
of the receptor for AIDS retrovirus. Nature 1984, 312:763-767.
43. Cameron PU: Science 1992, 257:383-387.
44. Frankel SS: Science 1996, 272:115-117.
45. Austyn JM, Steinman RM: The passenger leukocytes – a fresh
look. Transplantation reviews 1988, 2:139-176.
46. Larsen CP, Steinman RM, Witmer-Pack M, Hankins DF, Morris PJ,
Austyn JM: Migration and maturation of Langerhans cells in

skin transplants and explants. J Exp Med 1990, 172:1483-1493.
47. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engle-
man EG, Levy R: Vaccination of patients with B-cell lymphoma
using autologous antigen-pulsed dendritic cells. Nat Med 1996,
2:52-58.
48. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G,
Schadendorf D: Vaccination of melanoma patients with pep-
tide- or tumor lysate-pulsed dendritic cells. Nat Med 1998,
4:328-332.
49. Banchereau J, Shuler-Thumer B, Paluka AK, Schuler G: Dendritic
cells as vectors for therapy. Cell 2001, 106:271-274.
50. Boczkowski D, Nair SK, Snyder D, Gilboa E: Dendritic cells pulsed
with RNA are potent antigen-presenting cells in vitro and in
vivo. J Exp Med 1996, 184:465-472.
51. Gyure LA, Barfoot R, Denham S, Ha II JG: Immunity to a syn-
geneic sarcoma induced in rats by dendritic lymph cells
exposed to the tumor either in vivo or in vitro. Br J Cancer
1987, 55:17-20.
52. Knight SC, Hunt R, Dore C, Medawar PB: Influence of dendritic
cells on tumor growth. Proc Natl Acad Sci USA 1985, 82:4495-4497.
53. Greenberg PD: Adoptive T cell therapy of tumors: Mecha-
nisms operative in the recognition and elimination of tumor
cells. Adv in Immunol 1991, 49:281.
54. Nair S, Babu JS, Dunham RG, Kanda P, Burke RL, Rouse BT: Induc-
tion of primary, anti viral cytotoxic, and proliferative
responses with antigens administered via dendritic cells. J
Virol 1993, 67:4062-4069.
55. Rouse RJ, Nair SK, Lydy SL, Bowen JC, Rouse BT: Induction in vitro
of primary cytotoxic T-lymphocytes responses with DNA
encoding herpes simplex virus proteins. J Virol 1994,

68:5685-5689.
56. Zou W: Stromal-derived factor-1 in human tumors recruits
and alters the function of plasmacytoid precursor dendritic
cells. Nat Med 2001, 7:1339-1346.
57. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM,
Nadaf S, Kavanaugh D, Carbone DP: Production of vascular
endothelial growth factor by human tumors inhibits the
functional maturation of dendritic cells [published erratum
appears in Nat Med 1996 Nov;2(11):1267]. Nat Med 1996,
2:1096-1103.
58. Gabrilovich DI, Ciernik IF, Carbone DP: Dendritic cells in antitu-
mor immune responses. I. Defective antigen presentation in
tumor-bearing hosts. Cell Immunol 1996, 170:101-110.
59. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP:
Decreased antigen presentation by dendritic cells in patients
with breast cancer. Clin Cancer Res 1997, 3:483-490.
60. Gabrilovich DI, Nadaf S, Corak J, Berzofsky JA, Carbone DP: Den-
dritic cells in antitumor immune responses. II. Dendritic
cells grown from bone marrow precursors, but not mature
DC from tumor-bearing mice, are effective antigen carriers
in the therapy of established tumors. Cell Immunol 1996,
170:111-119.
61. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux
C, Blay JY: Inhibition of the differentiation of dendritic cells
from CD34(+) progenitors by tumor cells: role of inter-
leukin-6 and macrophage colony-stimulating factor. Blood
1998, 92:4778-4791.
62. Chomarat P, Banchereau J, Davoust J, Palucka AK: IL-6 switches the
differentiation of monocytes from dendritic cells to
macrophages. Nat Immunol 2000, 1:510-514.

63. Kelsall BL: Distinct populations of dendritic cells are present
in the subepithelial dome and T cell regions of the murine
peyers patch. J Exp Med 1996, 183:237-247.
64. Kelsall BL, Strober W: Dendritic cells of the gastrointestinal
tract. Springer Semin Immunopathol 1997, 18:409.
65. Kelsall BL, Biron ChA, Sharma O, Kaye PM: Dendritic cells at the
host-pathogen interface. Nature immunology 2002, 3:699-702.
66. Erickson KL, Hubbard NE: Probiotic immunomodulation in
health and disease. J Nutr 2000, 130:403-409S.
67. Ahrne S, Nobacek S, Jeppsson B, Adlerberth I, Wold AE, Molin G:
The normal Lactobacillus flora of healthy human rectal and
oral mucosa. J Appl Microbial 1998, 85:88.
68. Guarner F, Schaafsma GJ: Probiotics Int J Food Microbial 1998, 39:237.
69. Curiel T, Morris C, Brumlik M, Landry S, Mohamadzadeh M: Pep-
tides identified through phage display direct immunogenic
antigen to dendritic cells. Submitted for publication 2003.
70. Lucas A, McPherson G: Langerhans cells: immigrants or
residents? Nature Immunology 2003, 3:1125-1126.
71. Filgueira L, Nestle FO, Rittig M, Joller HU, Groscuth P: Human den-
dritic cells phagocytose and process borrelia burgdorferi. J
Immunol 1996, 157:2998-3005.
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Journal of Immune Based Therapies and Vaccines 2004, 2 />Page 11 of 11
(page number not for citation purposes)
72. Guebre-Xabier M: Immunostimulant patch containing heat-
labile enterotoxin from Escherichia coli enhances immune
responses to inject influenza virus vaccine through activation
of skin dendritic cells. J virology 2003, 77:5218-5225.
73. Glenn G: Transcutaneously immunization: a human vaccine
delivery strategy using patch. Nat Med 2000, 6:1403-1406.
74. Guerena-Burgueno F: Safty and immunogenicity of prototype
enterotoxigenic Escherichia coli vaccine administrated
transcutaneously. Infect Immun 2002, 70:1874-1880.
75. Matthews K, Leong CM, Baxter L, Inglis E, Yun K, Blackstrom B,
Doorbar J, Hibma M: Depletion of Langerhans cells in Human
Papilloma virus type 16-infected skin is associated with E6-
mediated down regulation of E-cadhedrin. J Virol 2003,
77:8378-8385.